The microdialysis technique has been developed to monitor the dynamic extracellular neurotransmitter levels in the Rhesus monkey brain. This technique enables the characterization of the neurochemical and neuropharmacological correlates, of cortical regulation of subcortical structures, and frontal and temporal lobe functional interaction. A guide cannula system which aids in the accurate and repeatable placement of probes has been shown to be effective in both sedate and awake behaving monkeys. Extracellular dopamine levels were detected in the caudate nucleus and prefrontal cortex of the sedate monkey, however, DA was much lower and more difficult to detect in cortex than in the caudate. DA found in the neostriatum, was sensitive to both K+ evoked stimulation and to neuronal blockade by tetrodotoxin infusions, confirming that the observed DA levels were neuronally released from the synapse rather than released from damaged synaptic vesicles from insertion of the microdialysis probe. DA release was manipulated pharmacologically by infusion of amphetamine and cocaine through the dialysis probe. In both the cortex and the striatum DA levels were dramatically increased. Remarkably, this observed increase could be seen In the cortex even when prior to the amphetamine or cocaine infusion baseline DA levels were below detection. Recently, we have been able to analyze for the presence of amino acids, such as, glutamate, aspartate, and gaba in our dialysate samples. These were more consistently detected in the cortex and like dopamine increased significantly with amphetamine and cocaine infusion. We also examined what effects increasing cortical dopamine would have on subcortical targets of the mesocortical dopamine system. Prefrontal cortical infusion of amphetamine or cocaine resulted in significant reduction in striatal DA release. These data demonstrate that in primates cortico-caudate projections regulate the release of striatal DA. We are now in the process of determining whether this reduction is a result of the increase in cortical DA, or from the increase in amino acids, such glutamate. In addition, we are examining whether other cortico-caudate projections, such as those from the parietal or temporal lobe regions have similar regulatory effects. In order to investigate neurochemical and neuropharmacological correlates of frontal and temporal lobe function we have extended our dialysis procedures to the awake behaving monkey. In the awake monkey we have been able to establish stable baseline levels for acetylcholine, DA and some of its metabolites, and some of the amino acid neurotransmitters. In contrast to that seen in the sedate monkey DA in the caudate was substantially lower and sometimes more difficult to detect. Acetylcholine, however, was easily found in both areas, but, levels appear to be less than that found in the rat. More interestingly our preliminary data suggest that there may be a strong correlation of glutamate levels with performance on a cognitive task. Thus this would be the first demonstration of localized neurotransmitter turnover correlated with cognitive stimulation.